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https://www.readbyqxmd.com/read/28719094/discovery-and-characterization-of-a-novel-tryptophan-hydroxylase-1-inhibitor-as-a-prodrug
#1
Hailong Shi, Yaya Cui, Yifei Qin
Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2 are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH...
July 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28716530/genetic-association-analysis-of-serotonin-and-signal-transduction-pathways-in-suicide-attempters-from-an-italian-sample-of-psychiatric-patients
#2
Maurizio Pompili, Giovanna Gentile, Catia Scassellati, Cristian Bonvicini, Marco Innamorati, Denise Erbuto, Franco Montebovi, Giuseppe Ducci, Alberto Forte, Eleonora De Pisa, Stefano Ferracuti, Gianluca Serafini, Vincenzo De Luca, Mario Amore, Maurizio Simmaco, Paolo Girardi
Genetic factors have been reported to contribute to the liability of suicide. We aimed to investigate functional polymorphisms in eight genes (serotonin transporter, SLC6A4; receptors, 5HTR1A, 1B, 5HTR2A; Tryptophan Hydroxylase, TPH1, TPH2; Monoamine Oxidase, MAOA and G Protein Subunit Beta 3, GNB3) to investigate their predictive value for suicide. The possible confounding effects of gender and phenotypic patients dissection were also valued. A sample of 111 consecutive psychiatric inpatients was recruited and assessed using specific psychometric instruments...
July 14, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28706142/stress-inhibits-tryptophan-hydroxylase-expression-in-a-rat-model-of-depression
#3
Yi Chen, Haixia Xu, Mingyue Zhu, Kun Liu, Bo Lin, Ruxian Luo, Chuanbai Chen, Mengsen Li
Serotonin (5-hydroxytryptamine, 5-HT) dysfunction is associated with the pathophysiology of depression. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis, is believed to have essential role in many mental disorders, including depression. In the present study, we generated a rat model of depression by exposing the animals to stress, and the rats were then treated with paroxetine. The results indicated that the concentration of 5-HT in the brain and liver tissues were significantly lower in the rat model of depression than in healthy or treated rats...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28687505/xiaochaihutang-attenuates-depressive-anxiety-like-behaviors-of-social-isolation-reared-mice-by-regulating-monoaminergic-system-neurogenesis-and-bdnf-expression
#4
Jie Ma, Fang Wang, Jingyu Yang, Yingxu Dong, Guangyue Su, Kuo Zhang, Xing Pan, Ping Ma, Tingshuo Zhou, Chunfu Wu
ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT), as a classical herbal formula for the treatment of "Shaoyang syndrome" has been demonstrated to exert an antidepressant effect in multiple animal models of depression as shown in our previous studies. However, the effects of XCHT on social isolation (SI)-reared mice have not been investigated. This study aims to explore the effects of XCHT on depressive/anxiety-like behaviors of SI-reared mice, and its implicated mechanisms, including alterations in the monoaminergic system, neurogenesis and neurotrophin expression...
July 5, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28650979/expression-of-cerebral-serotonin-related-to-anxiety-like-behaviors-in-c57bl-6-offspring-induced-by-repeated-subcutaneous-prenatal-exposure-to-low-dose-lipopolysaccharide
#5
Pei-Tan Hsueh, Hsuan-Han Wang, Chiu-Lin Liu, Wei-Fen Ni, Ya-Lei Chen, Jong-Kang Liu
Prenatal exposure to lipopolysaccharide (LPS), which likely occurs due to infection or contact with environmental allergens during pregnancy, is a proposed risk factor that induces anxiety- and autism spectrum disorder-like behaviors in offspring. However, the molecular and behavioral changes in offspring after maternal immune activation have not been completely identified. We hypothesized that a subcutaneous injection of LPS in a pregnant mouse would induce changes in cerebral serotonin (5-HT) in parallel to the appearance of anxiety-like behaviors in the dam's offspring...
2017: PloS One
https://www.readbyqxmd.com/read/28630479/attention-cognitive-control-and-motivation-in-adhd-linking-event-related-brain-potentials-and-dna-methylation-patterns-in-boys-at-early-school-age
#6
Hartmut Heinrich, Juliane Grunitz, Valeska Stonawski, Stefan Frey, Simone Wahl, Björn Albrecht, Tamme W Goecke, Matthias W Beckmann, Johannes Kornhuber, Peter A Fasching, Gunther H Moll, Anna Eichler
In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28590957/genetic-moderation-of-cocaine-subjective-effects-by-variation-in-the-tph1-tph2-and-slc6a4-serotonin-genes
#7
Michelle A Patriquin, Sara C Hamon, Mark J Harding, Ellen M Nielsen, Thomas F Newton, Richard De La Garza, David A Nielsen
OBJECTIVE: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. METHODS: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion...
June 6, 2017: Psychiatric Genetics
https://www.readbyqxmd.com/read/28579486/no-effect-of-c1473g-polymorphism-in-the-tryptophan-hydroxylase-2-gene-on-the-response-of-the-brain-serotonin-system-to-chronic-fluoxetine-treatment-in-mice
#8
Ekaterina Y Bazhenova, Nadezhda A Sinyakova, Elizabeth A Kulikova, Irina A Kazarinova, Daria V Bazovkina, Raul R Gainetdinov, Alexander V Kulikov
Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block serotonin transporter (SERT) and increase serotonin (5-HT) level in the synaptic cleft. The interaction between SERT and the key enzyme of 5-HT synthesis in the brain, tryptophan hydroxylase 2 (TPH2), is essential to maintain the brain 5-HT level. The G allele of C1473G polymorphism in Tph2 gene decreases enzyme activity by half in mouse brain. Here we studied effect of C1473G polymorphism on the reaction of brain 5-HT system to chronic fluoxetine treatment (120mg/l in drinking water, for 3 weeks) in adult males of the congenic B6-1473C and B6-1473G mouse lines with high and low enzyme activity, respectively...
July 13, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28555406/investigation-of-previously-implicated-genetic-variants-in-chronic-tic-disorders-a-transmission-disequilibrium-test-approach
#9
Mohamed Abdulkadir, Douglas Londono, Derek Gordon, Thomas V Fernandez, Lawrence W Brown, Keun-Ah Cheon, Barbara J Coffey, Lonneke Elzerman, Carolin Fremer, Odette Fründt, Blanca Garcia-Delgar, Donald L Gilbert, Dorothy E Grice, Tammy Hedderly, Isobel Heyman, Hyun Ju Hong, Chaim Huyser, Laura Ibanez-Gomez, Ewgeni Jakubovski, Young Key Kim, Young Shin Kim, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett Leventhal, Andrea G Ludolph, Marcos Madruga-Garrido, Athanasios Maras, Pablo Mir, Astrid Morer, Kirsten Müller-Vahl, Alexander Münchau, Tara L Murphy, Kerstin J Plessen, Veit Roessner, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Jennifer Tübing, Els van den Ban, Frank Visscher, Sina Wanderer, Martin Woods, Samuel H Zinner, Robert A King, Jay A Tischfield, Gary A Heiman, Pieter J Hoekstra, Andrea Dietrich
Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort...
May 29, 2017: European Archives of Psychiatry and Clinical Neuroscience
https://www.readbyqxmd.com/read/28537235/-serotonergic-genes-in-the-development-of-anxiety-depression-like-state-and-pathology-of-aggressive-behavior-in-male-mice-rna-seq-data
#10
N N Kudryavtseva, D A Smagin, I L Kovalenko, A G Galyamina, G B Vishnivetskaya, V N Babenko, Yu L Orlov
In course of daily agonistic interactions, mice tend to stratify into those with chronic social defeats and those that repeatedly display aggression, which lead to the development of mixed anxiety/depression-like state and the pathology of aggressive behavior, respectively. Using the data of whole transcriptome analysis (RNA-seq), the changes in the expression of serotonergic genes involved in the synthesis, inactivation, and reception of serotonin, as well as of the Creb1 (transcription factor) gene and the Bdnf (brain-derived neurotrophic factor) gene were detected in the striatum (STR), ventral tegmental area (VTA), midbrain raphe nuclei (MRN), hypothalamus (HYP), and hippocampus (HIP) of defeated and aggressive male mice...
March 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28529483/identification-of-a-novel-allosteric-inhibitory-site-on-tryptophan-hydroxylase-1-enabling-unprecedented-selectivity-over-all-related-hydroxylases
#11
Mike Petrassi, Rob Barber, Celine Be, Sarah Beach, Brian Cox, Anne-Marie D'Souza, Nick Duggan, Martin Hussey, Roy Fox, Peter Hunt, Gabor Jarai, Takatoshi Kosaka, Paul Oakley, Viral Patel, Neil Press, David Rowlands, Clemens Scheufler, Oliver Schmidt, Honnappa Srinivas, Mary Turner, Rob Turner, John Westwick, Alison Wolfreys, Nuzhat Pathan, Simon Watson, Matthew Thomas
Pulmonary arterial hypertension (PAH) has demonstrated multi-serotonin receptor dependent pathologies, characterized by increased tone (5-HT1B receptor) and complex lesions (SERT, 5-HT1B, 5-HT2B receptors) of the pulmonary vasculature together with right ventricular hypertrophy, ischemia and fibrosis (5-HT2B receptor). Selective inhibitors of individual signaling elements - SERT, 5-HT2A, 5HT2B, and combined 5-HT2A/B receptors, have all been tested clinically and failed. Thus, inhibition of tryptophan hydroxylase 1 (TPH1), the rate limiting step in 5-HT synthesis, has been suggested as a more broad, and thereby more effective, mode of 5-HT inhibition...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28464229/functional-characterization-of-the-neuron-restrictive-silencer-element-in-the-human-tryptophan-hydroxylase-2-gene-expression
#12
Yukino Nawa, Hanae Kaneko, Masayuki Oda, Masaaki Tsubonoya, Tomoko Hiroi, Maria Teresa Gentile, Luca Colucci-D'Amato, Ryoya Takahashi, Hiroaki Matsui
Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal serotonin. Although previous studies suggest that TPH2 NRSE (neuron-restrictive silencer element) functions as a negative regulator dependent on NRSF (neuron-restrictive silencer factor) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2...
May 2, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28456685/association-of-regulatory-tph2-polymorphisms-with-higher-reduction-in-depressive-symptoms-in-children-and-adolescents-treated-with-fluoxetine
#13
Patricia Gassó, Natalia Rodríguez, Daniel Boloc, Ana Blázquez, Teresa Torres, Ana Gortat, Maria Teresa Plana, Amalia Lafuente, Sergi Mas, Joan Albert Arnaiz, Luisa Lázaro
Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine...
April 26, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28443016/genetics-of-aggression-in-alzheimer-s-disease-ad
#14
Walter J Lukiw, Evgeny I Rogaev
Alzheimer's disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28413824/perturbation-of-serotonin-homeostasis-during-adulthood-affects-serotonergic-neuronal-circuitry
#15
Marta Pratelli, Sara Migliarini, Barbara Pelosi, Francesco Napolitano, Alessandro Usiello, Massimo Pasqualetti
Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2(fl)°(x) conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28386236/metabolic-response-of-visceral-white-adipose-tissue-of-obese-mice-exposed-for-5-days-to-human-room-temperature-compared-to-mouse-thermoneutrality
#16
Inge van der Stelt, Femke Hoevenaars, Jitka Široká, Lidwien de Ronde, David Friedecký, Jaap Keijer, Evert van Schothorst
Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28342337/nice-guys-homozygocity-for-the-tph2-703g-t-rs4570625-minor-allele-promotes-low-aggressiveness-and-low-anxiety
#17
Kariina Laas, Evelyn Kiive, Jarek Mäestu, Mariliis Vaht, Toomas Veidebaum, Jaanus Harro
BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. METHODS: We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts...
June 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28320136/association-between-gene-polymorphism-and-depression-in-parkinson-s-disease-a-case-control-study
#18
Jinhua Zheng, Xinglong Yang, Quanzhen Zhao, Sijia Tian, Hongyan Huang, Yalan Chen, Yanming Xu
OBJECTIVE: To investigate possible associations of Parkinson's disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. METHODS: A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. RESULTS: Of 330 patients, 125 (37...
April 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28264500/geneanalytics-pathway-analysis-and-genetic-overlap-among-autism-spectrum-disorder-bipolar-disorder-and-schizophrenia
#19
Naveen S Khanzada, Merlin G Butler, Ann M Manzardo
Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e...
February 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28210624/rna-sequencing-analysis-reveals-interactions-between-breast-cancer-or-melanoma-cells-and-the-tissue-microenvironment-during-brain-metastasis
#20
Ryo Sato, Teppei Nakano, Mari Hosonaga, Oltea Sampetrean, Ritsuko Harigai, Takashi Sasaki, Ikuko Koya, Hideyuki Okano, Jun Kudoh, Hideyuki Saya, Yoshimi Arima
Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases...
2017: BioMed Research International
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